tbuckley/cabot-search huggingface dataset:
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

Multiple cancer therapeutics targeting c-Met receptor kinase have been developed, but clinical activity with this drug class has been limited to small subsets of patients with MET amplification. ABBV-399, a novel antibody-drug conjugate therapeutic, delivers a potent cytotoxin to c-Met overexpressing tumor cells and kills c-Met positive and MET-amplified tumor cell lines regardless of reliance on MET signaling. This activity extends to cell line and PDX xenografts, including models refractory to other c-Met inhibitors. ABBV-399 has advanced to Phase 1 studies, where it has been well tolerated and has produced objective responses in c-Met expressing NSCLC patients.As more BET/BRD4 inhibitors enter the Phase I/II clinical setting, it becomes increasingly important to understand how they compare against each other. One way to achieve this is the alignment of pharmacodynamic biomarkers measured across the programs. Yeh and colleagues have identified CCR2 and CD180 mRNA as promising clinical biomarker candidates for whole blood and hematologic tumor samples for this class of inhibitors. Robust downregulation of these biomarkers was observed in tumor cell lines, xenograft models, rodent blood, and human blood studies at efficacious doses and/or at clinically relevant concentrations of AZD5153, a novel BRD4 inhibitor.Lung cancer, especially NSCLC, is the leading cause of cancer death around the world. To validate drug targets selectively for NSCLC, Zhou and colleagues focused on UBE2F, an E2-conjugating enzyme for neddylation modification. The authors report that UBE2F is overexpressed in NSCLC, which is correlated with poor patient survival. Functional studies revealed that UBE2F, by activating Cullin RING ligase-5, selectively promotes lung cancer cell survival by ubiquitylating and degrading proapoptotic protein NOXA via a novel K11 linkage. This study validates UBE2F as an attractive anticancer target and provides a rationale for future discovery of specific UBE2F inhibitors against NSCLC.Luminal A breast cancers have the best prognosis among the main molecular subtypes and may not benefit from adjuvant chemotherapy. Using a formal prospective-retrospective study that included 709 breast cancers from the DBCG77B randomized trial, tested with readily available immunohistochemistry methods, Nielsen and colleagues show that in contrast to patients with basal-like or Luminal B cancers, patients with Luminal A breast cancers obtained no benefit from chemotherapy (interaction test significant for the prespecified primary analysis). These patients, despite being node-positive and/or having large primary tumors in this trial, do not appear to benefit from adjuvant cyclophosphamide-based chemotherapy.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

Wang and colleagues describe the first-in-human phase I clinical trial using CD30-specific chimeric antigen receptor-modified T cells (CART-30) in patients with relapsed or refractory Hodgkin lymphoma (HL). Their results demonstrate that treatment is well tolerated, without severe toxicity, and yielded a 39% objective response in HL patients, even those who failed with autologous stem-cell transplantation or brentuximab treatment. Responses correlated with efficient trafficking of CART-30 cells in tumor sites and sustained proliferation.Small-cell lung cancer (SCLC) is the most aggressive and lethal lung cancer subtype for which novel treatment options are of urgent need. Immune checkpoint blockade targeting the programmed death ligand-1 (PD-L1, CD274) has shown promising clinical efficacy in SCLC patients. George and colleagues studied the genomic locus of CD274 and report on a subset of SCLC tumors (1.9%, 4/210 cases) that exhibit massive expression of PD-L1 caused by focal amplification of CD274. Such tumors may be particularly susceptible to immune checkpoint blockade.Biomarkers capable of identifying stage III colorectal cancer (CRC) patients at high-risk of chemotherapy resistance, and thus relapse, remains an unmet clinical demand. Lack of response to chemotherapeutics has been ascribed to defective apoptosis. Using an integrative stepwise approach, Salvucci and colleagues investigated the clinical utility of a mathematical model of caspase activation for identifying patient-specific risk of unfavorable outcomes. Among all clinicopathological, demographic, and molecular predictors analyzed, enriched-apoptosis systems modeling delivered the highest ranking independent prognostic biomarker. Furthermore, apoptosis modeling can be combined with molecular tumor subtyping to further refine risk predictions. These findings demonstrate diagnostic tools for stage III CRC patients that could deliver superior quality of care by personalizing cancer treatment.Paclitaxel treatment frequently causes peripheral neuropathy, an adverse event that can limit treatment course and lead to permanent symptoms affecting quality of life. Polymorphisms in EPHA genes have been associated with paclitaxel neuropathy, but a large part of the interindividual variation remains unexplained. By performing targeted exon sequencing of candidate genes Apellániz-Ruiz and colleagues found that patients carrying low-frequency nonsynonymous coding variants in EPHA5/6/8 contributed to paclitaxel-induced neuropathy susceptibility. Furthermore, these genes also might be relevant neuropathy markers for other neurotoxic drugs due to the involvement of Eph receptors in neuronal functions.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

Salt-inducible kinase 2 (SIK2) is overexpressed in 30% of ovarian cancers and regulates centrosome splitting, mitotic progression, and activation of PI3K. A small-molecule inhibitor of SIK2 (ARN-3236) blocks the activity of SIK2 kinase, inhibits growth of ovarian cancer cell lines, and enhances sensitivity to paclitaxel in cell culture and in xenografts. ARN-3236 produces nuclear-centrosome dissociation, inhibits centrosome splitting, blocks mitotic progression, induces polyploidy, reduces AKT/survivin signaling, and triggers apoptotic cell death. Thus, ARN-3236 appears to be a drug with promise for enhancing primary treatment of ovarian cancers.Mameri and colleagues report that cytidine deaminase (CDA) expression is downregulated in about 60% of tumors, mostly due to DNA methylation. Immunohistochemistry assessments of CDA expression status defined two new subgroups of tumors: CDA-deficient tumors and CDA-proficient tumors. CDA-deficient tumor cells, but not CDA-proficient tumor cells, present a marked susceptibility to aminoflavone, indicating that CDA expression status could be used to guide anticancer therapy. These results constitute a proof-of-concept that CDA deficiency may turn out to be a new predictive marker of susceptibility to antitumor drugs, thus opening up new possibilities for treating cancer.Patients with glioblastoma (GBM) have a median survival of &lt;15 months despite surgical resection, high-dose radiation and chemotherapy with temozolomide (TMZ). Cytomegalovirus (CMV) proteins are expressed in over 90% of sampled GBM and expression is restricted to glioma cells not surrounding normal brain tissue. Batich and colleagues targeted the CMV antigen pp65 using dendritic cells (DCs) in combination with dose-intensified temozolomide (TMZ) and evaluated patient antitumor immune responses and survival. Despite increases in regulatory T cells after TMZ, patients treated with pp65-DCs showed increased pp65 immunity and long-term survival extending beyond predicted rates. Randomized studies on the prevention of generated regulatory T cells in the context of TMZ treatment and CMV targeting are under way.The lncRNA PVT1 is an important oncogene in human tumors; however, the mechanisms underlying the PVT1 functions remain elusive. Xu and colleagues demonstrate a reciprocal link between PVT1 and FOXM1 in gastric cancer (GC). PVT1 binds to the FOXM1 protein and enhances its stability, fulfills its functions in a FOXM1-mediated manner. Moreover, FOXM1 binds directly to and constitutively transactivates the PVT1 promoter. The authors report a novel mechanism by which transcript-induced lncRNA facilitate mRNA function by stabilizing a transcript-coding protein posttranscriptionally. PVT1 expression may be a useful biomarker for GC prognosis, and the PVT1-FOXM1 loop could be a therapeutic target.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

The clinical impact of mechanisms of acquired resistance to anti-EGFRs in mCRC is poorly understood. In chemorefractory patients treated with anti-EGFRs, Pietrantonio and colleagues performed NGS and MET/HER2 in situ hybridization on tumor samples obtained at baseline and at disease progression. Matched ctDNA was also analyzed. RAS and BRAF mutations and HER2 and MET amplifications were the most frequent alterations, but concordance among tumor and liquid biopsies was not always detectable. Intra- and interlesion heterogeneity of resistance mechanisms was observed. These results could have clinical implications to select the most appropriate therapy in patients who develop acquired resistance to anti-EGFRs.A major challenge for cancer immunotherapy has been the eradication of large solid tumors. In a major advance towards this goal, Slaney and colleagues describe an approach using adoptive cell transfer and an oncolytic viral vaccine, which led to extensive T-cell proliferation and recruitment of endogenous immunity to mediate complete and durable regression of established tumors in mice. Notably, the study was performed in syngeneic, self-antigen models, which permitted the stringent preclinical assessment of efficacy and potential toxicities of this approach, to enable progression of the approach towards the clinic.Genomic and transcriptomic analysis are starting to define the landscape of male breast cancer. In an analysis of over 700 male breast cancer cases across four independent datasets at the transcriptomic and immunohistochemical levels, increased expression of translational initiation pathway genes, eIF4E and eIF5, were independent predictors of reduced survival. Samples from a male patient with breast cancer who was treated with an investigational combination of BEZ235 and everolimus, which target this pathway, showed a marked reduction in eIF4E and eIF5 expression, accompanied by improved survival, suggesting this pathway may be tractable.Hepatocellular carcinoma (HCC) is the sixth most common cancer in the world and the third most common cause of cancer-related death in the Asia-Pacific region. Sorafenib monotherapy, the current standard of care for advanced HCC, provides only modest survival benefit; more effective systemic therapies are needed. Results reported by Yau and colleagues from a phase I/II clinical trial of foretinib as a first-line monotherapy for advanced HCC in Asian patients show promising antitumor activity with acceptable safety and tolerability. Further investigation of the relative efficacy of foretinib and standard of care treatment in advanced HCC is warranted.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

Osteosarcoma (OS) is a highly aggressive bone tumor of childhood and adolescence for which alternative therapeutic options are urgently needed. Baglio and colleagues demonstrate that osteosarcoma cells release TGFβ-rich extracellular vesicles that educate mesenchymal stem cells to support tumor progression through IL6 secretion. Therapeutic blockade of IL6R prevents lung metastasis formation induced by tumor-educated MSCs in an orthotopic xenograft mouse model of osteosarcoma. OS patients have activated TGFβ and stroma-dependent IL6 signaling and display elevated circulating levels of EV-associated TGFβ. This study provides the basis for the use of IL6 and TGFβ blocking agents as new therapeutic strategy for osteosarcoma.Robust preclinical models of pediatric acute lymphoblastic leukemia (ALL) are essential in prioritizing novel drugs for clinical evaluation. Jones and colleagues developed bioluminescence imaging (BLI)-enabled ALL patient-derived xenografts (PDXs), and compared BLI with traditional flow cytometric methods in evaluating preclinical drug efficacy. BLI monitored remission with greater range than PB measurements and allowed measurement of leukemia in discrete organs. Correlating BLI and flow cytometry data enabled noninvasive assessment of minimal residual disease, as well as the establishment of novel scoring parameters. This article highlights the utility of BLI in enabling stringent evaluation of drug efficacy in ALL PDXs, ensuring that only the most promising agents are put forward for clinical assessment.Implementation of primary high-risk HPV testing in cervical screening results in better protection against cervical (pre)cancer. However, its specificity for clinically meaningful disease is lower than that of current cytology-based screening. Therefore, molecular markers that identify clinically relevant lesions would reduce over-referral and overtreatment. Following a genome-wide approach, Verlaat and colleagues identified three novel methylation markers located at a chromosomal gain at 3q, which showed an excellent clinical performance for detection of cervical (pre)cancer in cervical scrapes. These markers enable the detection of advanced precursor lesions with a high short-term progression risk to cancer. These findings could greatly improve cervical screening.Many Gleason pattern 3 (Gp3) prostate cancers detected on biopsy are indolent and do not require further therapy, but a subset of these patients will have or develop higher-grade cancers. Sowalsky and colleagues establish that a subset of Gp3 tumors emerge early from a common precursor lesion that also can progress to Gp4. These Gp3 tumors have molecular features, including tumor suppressor losses that may distinguish them from indolent Gp3, and which may be used clinically as biomarkers to identify patients with only Gp3 on biopsy who are at increased risk of having occult Gp4.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

Defects in homologous recombination repair genes (e.g., BRCA1 and BRCA2 mutations) can sensitize tumors to poly(ADP-ribose) polymerase (PARP) inhibition through synthetic lethality. This phase I–II study was the first to evaluate single-agent oral rucaparib, a potent PARP inhibitor, at multiple doses in patients with advanced solid tumors (Part 1; phase I), establish the recommended phase II dose (RP2D) of 600 mg twice daily, and evaluate the RP2D in patients with platinum-sensitive, high-grade ovarian carcinoma (HGOC) associated with a germline BRCA1/2 mutation (Part 2A; phase II). Rucaparib was tolerable and had robust antitumor activity in patients with platinum-sensitive germline BRCA1/2-mutated HGOC.Germinal center B-cell (GCB) has a better prognosis than non-GCB diffuse large B-cell lymphoma (DLBCL) to upfront therapy. Cell-of-origin (COO) determination using gene expression profiling (GEP) is more sensitive, reproducible, and robust than immunohistochemistry. Czuczman and colleagues designed a randomized study using COO-based subtyping to elucidate differences in activity of lenalidomide over salvage monotherapy in relapsed/refractory DLBCL. Lenalidomide elicited higher ORR and longer PFS in non-GCB patients (most pronounced in ABC-designated patients). These results provide an additional rationale for the ongoing phase 3 trial, ROBUST (NCT02285062), of lenalidomide plus immunochemotherapy versus immunochemotherapy alone in patients with treatment-naive GEP-selected ABC-subtype DLBCL.The improvement of imaging and therapeutic targeting of tumors requires the identification of novel target-specific tracers. To address HNSCC tumors, Altmann and colleagues performed alternating biopanning on membrane proteome of HNO97 tumor cells fractionated by the ProteomeLab PF2D system and corresponding HNO97 cells using a sunflower trypsin inhibitor1-based phage display (SFTI8Ph) library. A novel ITGαvβ6-binding peptide (SFITGv6) was identified providing high stability and demonstrating affinity for ITGαvβ6-positive HNSCC and other carcinomas. SFITGv6 accumulated in tumor tissues but not in normal tissues or inflammatory lesions, and thus represents a promising tracer for imaging and endoradiotherapy.Deubiquitylating (DUB) enzymes have emerged as potential therapeutic targets. Das and colleagues examined the functional significance of DUB enzyme USP1 in multiple myeloma (MM) using an irreversible USP1 inhibitor SJB3-019A. USP1 is highly expressed in patient multiple myeloma (MM) cells. USP1 blockade with SJB3-019A decreases the viability of MM cells, inhibits DNA repair and USP1/ID/Notch/Sox pathways, and overcomes bortezomib-resistance. SJB induced generation of more mature and differentiated plasma cells. Combination of SJB with bortezomib, ACY1215, lenalidomide, or pomalidomide triggers synergistic anti-MM activity. These preclinical data provide basis for clinical evaluation of USP1 inhibitors in MM to overcome proteasome inhibitor resistance.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

Treatment options for osteosarcoma remain anchored to surgery and conventional chemotherapy, and are in need of additional and less toxic approaches. Ratti and colleagues developed osteosarcoma models in immunocompetent mice and showed the therapeutic efficacy of trabectedin, a clinically approved marine-derived drug, in halting osteosarcoma growth and metastases. The action of trabectedin was dual: direct on neoplastic cells, inducing their differentiation, and indirect on the immune microenvironment, increasing the infiltration of T cells. However, the latter highly expressed the inhibitory immune checkpoint PD-1. Consistently, combination of trabectedin and anti PD-1 antibody resulted in the best therapeutic effect.The authors investigate whether epigenetic changes are involved in the response to tyrosine kinase inhibitor (TKI) treatment of epidermal growth factor receptor (EGFR) mutated lung cancer. To investigate methylation changes at the whole-genome level, Niu and colleagues applied methyl-sensitive cut counting sequencing (MSCC) in EGFR 19 deletion lung adenocarcinoma tissues before and after erlotinib treatment. A differential methylated region (DMR) of the GABBR2 gene was identified and validated based on the results of whole methylome profiling, and upregulation of GABBR2 rescued erlotinib-induced apoptosis in vitro. This research shows promise in the epigenetic study of EGFR-mutated lung adenocarcinoma treated with TKI.Conditioning strategies constitute a relatively unexplored and exciting opportunity to shape tumor fate by targeting the tumor microenvironment. In this study, Jaworski and colleagues adopted a strategy to remodel the stroma using hemin, a well-known inducer of the enzyme Heme Oxygenase-1, to counteract tumor development. Their results showcase a novel function of an already human-used drug as a means of boosting the endogenous response against prostate cancer, a major health care problem worldwide. In particular, hemin conditioning limits tumor development by simultaneously targeting both tumor vascularization and the cytotoxic T-cell responses.Hormone receptor positive (HR+)/human epidermal growth factor receptor 2-negative (HER2−) metastatic breast cancer (mBC) patients have limited treatment options. Targeting cyclin-dependent kinases (CDK), key components in the cell cycle that are dysregulated in many cancers, has emerged as a viable therapy strategy. In a phase II study of heavily pretreated refractory HR+/HER2− mBC patients, abemaciclib, a selective oral inhibitor of CDK4 and CDK6, exhibited promising single-agent activity and a safety profile that allowed for dosing on a continuous schedule. Abemaciclib may represent a possible therapy advancement for HR+/HER2− mBC patients.
Highlights of This Issue
Journal: Clinical Cancer Research (2017)

There is a clinical need for an improved approach for longitudinal noninvasive monitoring of the tumor burden in colorectal cancer (CRC) patients. Schøler and colleagues studied 371 plasma samples from 45 patients. Longitudinal samples revealed that postoperative ctDNA detection provides evidence of residual disease and identifies patients at very high risk of relapse. Furthermore, longitudinal surveillance enables early detection of relapse and informs about response to intervention. This work provides predictors of clinical outcome in CRC and has promising implications for personalized patient management during postsurgery follow-up.A high incidence of tumor metastasis poses a threat to the patient's survival; however, the underlying molecular mechanisms are largely unknown. Pang and colleagues characterize RCC2, a novel metastasis-related gene, and its role in lung adenocarcinoma (LUAD). They show that RCC2 is significantly associated with metastasis and could be an independent prognostic factor for LUAD. Furthermore, a series of in vitro and in vivo studies demonstrate that RCC2 can promote LUAD metastasis by inducing EMT via MAPK-JNK signaling. These findings offer novel insight about LUAD that may be beneficial to identify effective treatments against lung cancer.Accurate delineation of tumor margin is crucial for maximizing the efficacy of surgical treatment and the patient's subsequent quality of life. To achieve this, Lu and colleagues investigated the feasibility of using quantitative hyperspectral imaging (HSI) combined with machine learning-based tools as a diagnostic tool to delineate the cancer boundaries in surgical specimens of human patients with head and neck cancers (HNC). This study demonstrates the application of quantitative HSI as a sensitive and specific diagnostic tool for the detection and delineation of HNC in a wide variety of anatomic sites, which could be translated into the clinic application with the hope of improving clinical outcomes in the future.Histone deacetylase inhibitors (HDACi) are epigenome-targeting anticancer therapeutics for certain cancers; however, there is currently no clear strategy to reliably predict HDACi sensitivity. Chüeh and colleagues identify a novel mechanism by which HDACi induce apoptosis in tumor cells through induction of the ATF3 transcription factor and subsequent repression of BCLXL. This mechanism transcends tumor type, is measurable in patient samples in vivo, and defines the basis for sensitivity or resistance to HDACi. These findings establish a strategy for overcoming inherent resistance to HDACi by rational combination with BCL-XL inhibitors and define a framework for the identification of biomarkers predictive of HDACi response, including rapid assessment of ATF3 induction. Additionally, they have the potential to directly impact the clinical use of HDACi for the approved indications of CTCL and multiple myeloma, and for their ongoing clinical development in multiple malignancies.